Loss-of-function variant in KCNH3 is associated with global developmental delay, autistic behavior, insomnia, and...

The KCNH gene family encodes voltage-gated potassium (Kv) channels of the EAG subtype covering three subfamilies (Kv10-12). EAG channels are involved in the control of cardiac and neuronal excitation, and pathogenic variants in KCNH genes encoding Kv10 (eag) and Kv11 (erg) subfamily members cause a broad clinical spectrum ranging from cardiac arrhythmia to neurodevelopmental syndromes. However, no pathogenic variants have been hitherto reported for KCNH genes encoding Kv12 (elk) subfamily members.

Clinical, genomic, and functional studies were performed, including voltage-clamp experiments using heterologous channel expression in Xenopus oocytes.

We examined an eight-year-old girl presenting with global developmental delay, intellectual disability, autistic and aggressive behavior, hyperactivity, insomnia, and nocturnal seizures. Focal seizures were successfully treated with sulthiame, which reduced the occurrence of temporo-parietal spike-wave paroxysms. Trio exome sequencing revealed a heterozygous de novo missense variant, NM_012284.3:c.1112C>T; p.(Ala371Val), in KCNH3, which encodes the Kv channel α-subunit Kv12.2. The amino acid substitution associated with the KCNH3 variant identified in the patient is located at a site highly conserved in EAG channels. The analogous variant in KCNH2 causes long-QT-syndrome 2, and has also been associated with epilepsy. Electrophysiological characterization of the KCNH3 p.(Ala371Val) variant demonstrated loss-of-function of the mutant Kv12.2 channels and strongly reduced current amplitudes upon co-expression of wildtype and mutant channel subunits in a dominant-negative manner.

Our results propose KCNH3, which is primarily expressed in the nervous system, as a new disease gene associated with a neurodevelopmental phenotype including seizures.